The meaning of different forms of structural myocardial injury, immune response and timing of infarct necrosis and cardiac repair

Although a decline in the all-cause and cardiac mortality rates following myocardial infarction (MI) during the past 3 decades has been reported, MI is a major cause of death and disability worldwide. From a pathological point of view MI consists in a particular myocardial cell death due to prolonged ischemia. After the onset of myocardial ischemia, cell death is not immediate, but takes a finite period of time to develop. Once complete myocytes’ necrosis has occurred, a process leading to a healed infarction takes place. In fact, MI is a dynamic process that begins with the transition from reversible to irreversible ischemic injury and culminates in the replacement of dead myocardium by a fibrous scar. The pathobiological mechanisms underlying this process are very complex, involving an inflammatory response by several pathways, and pose a major challenge to ability to improve our knowledge. An improved understanding of the pathobiology of cardiac repair after MI and further studies of its underlying mechanisms provide avenues for the development of future strategies directed toward the identification of novel therapies. The chronologic dating of MI is of great importance both to clinical and forensic investigation, that is, the ability to create a theoretical timeline upon which either clinicians or forensic pathologists may increase their ability to estimate the time of MI. Aging of MI has very important practical implications in clinical practice since, based on the chronological dating of MI, attractive alternatives to solve therapeutic strategies in the various phases of MI are developing

Multicolor fluorescence technique to detect apoptotic cells in advanced coronary atherosclerotic plaques.

Apoptosis occurring in atherosclerotic lesions has been suggested to be involved in the evolution and the structural stability of the plaques. It is still a matter of debate whether apoptosis mainly involves vascular smooth muscle cells (vSMCs) in the fibrous tissue or inflammatory (namely foam) cells, thus preferentially affecting the cell-poor lipid core of the atherosclerotic plaques. The aim of the present investigation was to detect the presence of apoptotic cells and to estimate their percentage in a series of atherosclerotic plaques obtained either by autopsy or during surgical atherectomy. Apoptotic cells were identified on paraffinembedded sections on the basis of cell nuclear morphology after DNA staining and/or by cytochemical reactions (TUNEL assay, immunodetection of the proteolytic poly (ADP-ribose) polymerase-1 [PARP-1] fragment); biochemical procedures (identifying DNA fragmentation or PARP-1 proteolysis) were also used. Indirect immunofluorescence techniques were performed to label specific antigens for either vSMCs or macrophages (i.e., the cells which are most likely prone to apoptosis in atherosclerotic lesions): the proper selection of fluorochrome labeling allowed the simultaneous detection of the cell phenotype and the apoptotic characteristics, by multicolor fluorescence techniques. Apoptotic cells proved to be less than 5% of the whole cell population, in atherosclerotic plaque sections: this is, in fact, a too low cell fraction to be detected by widely used biochemical methods, such as agarose gel electrophoresis of low-molecular-weight DNA or Western-blot analysis of PARP-1 degradation. Most apoptotic cells were of macrophage origin, and clustered in the tunica media, near or within the lipid-rich core; only a few TUNEL-positive cells were labeled for antigens specific for vSMCs. These results confirm that, among the cell populations in atherosclerotic plaques, macrophage foam-cells are preferentially involved in apoptosis. Their death may decrease the cell number in the lipid core and generate a possibly defective apoptotic clearance: the resulting release of matrix-degrading enzymes could contribute to weakening the fibrous cap and promote the plaque rupture with the risk of acute ischemic events, while increasing the thrombogenic pultaceous pool of the plaque core

Second-Hand Smoke–Induced Cardiac Fibrosis Is Related to the Fas Death Receptor Apoptotic Pathway without Mitochondria-Dependent Pathway Involvement in Rats

Exposure to environmental tobacco smoke has been epidemiologically linked to heart disease among nonsmokers. However, the molecular mechanism behind the pathogenesis of cardiac disease is unknown. In this study, we found that Wistar rats, exposed to tobacco cigarette smoke at doses of 5, 10, or 15 cigarettes for 30 min twice a day for 1 month, had a dose-dependently reduced heart weight to body weight ratio and enhanced interstitial fibrosis as identified by histopathologic analysis. The mRNA and activity of matrix metalloprotease-2 (MMP-2), representing the progress of cardiac remodeling, were also elevated in the heart. In addition, we used reverse-transcriptase polymerase chain reaction and Western blotting to demonstrate significantly increased levels of the apoptotic effecter caspase-3 in treated animal hearts. Dose-dependently elevated mRNA and protein levels of Fas, and promoted apoptotic initiator caspase-8 (active form), a molecule of a death-receptor–dependent pathway, coupled with unaltered or decreased levels of cytosolic cytochrome c and the apoptotic initiator caspase-9 (active form), molecules of mitochondria-dependent pathways, may be indicative of cardiac apoptosis, which is Fas death-receptor apoptotic-signaling dependent, but not mitochondria pathway dependent in rats exposed to second-hand smoke (SHS). With regard to the regulation of survival pathway, using dot blotting, we found cardiac insulin-like growth factor-1 (IGF-1) and IGF-1 receptor mRNA levels to be significantly increased, indicating that compensative effects of IGF-1 survival signaling could occur. In conclusion, we found that the effects of SHS on cardiomyocyte are mediated by the Fas death-receptor–dependent apoptotic pathway and might be related to the epidemiologic incidence of cardiac disease of SHS-exposed non-smokers

Evaluación de la seguridad de la test de marcha de 6 minutos en pacientes en el pre-transplante cardiaco

FUNDAMENTO: O teste de caminhada dos 6 minutos (TC6) tem sido utilizado como forma de avaliação da capacidade funcional, estadiamento clínico e prognóstico cardiovascular. A segurança e o impacto metabólico são pouco descritos na literatura, principalmente em pacientes com insuficiência cardíaca grave, com indicação clínica para transplante cardiovascular. OBJETIVO: Avaliar a ocorrência de arritmias e alterações cardiovasculares durante o TC6. Correlacionar o desempenho no TC6 com o estadiamento clínico e prognóstico cardiovascular. MÉTODOS: Doze pacientes, sendo 10 masculinos, com idade de 52 ± 8 anos, foram submetidos à avaliação inicial. Realizaram o TC6 com monitoramento eletrocardiográfico por telemetria, sinais vitais e lactato. Foram acompanhados por 12 meses. RESULTADOS: Os pacientes percorreram 399,4 ± 122,5 (D, m), atingindo um esforço percebido (EP) de 14,3 ± 1,5 e variação de 34% na freqüência cardíaca basal. Dois pacientes apresentaram arritmia de maior gravidade pré-TC6 e não pioraram ante o esforço, quatro tiveram elevação significativa nos níveis de lactato sangüíneo (>5 mmol/dl), e três interromperam o exame. A distância percorrida evidenciou correlação com a fração de ejeção (%) e classificação funcional (NYHA). Após 12 meses de seguimento, três pacientes foram a óbito, e reinternaram-se sete por descompensação cardíaca. A relação (D/EP) e freqüência cardíaca de recuperação no segundo minuto (FCR2, bpm) foram inferiores no grupo-óbito. CONCLUSÃO: O comportamento clínico e eletrocardiográfico sugere que o método é seguro, mas pode ser considerado de alta intensidade para alguns pacientes com insuficiência cardíaca grave. Variáveis relacionadas ao desempenho no TC6 podem estar associadas com a mortalidade no seguimento de um ano. _______________________________________________________________________________________________________________ ABSTRACTBackground: The 6-minute walk test (6WT) has been used as a means of assessment of the functional capacity, clinical staging and cardiovascular prognosis. Its safety and metabolic impact have not been frequently described in the literature, especially in patients with severe heart failure with clinical indication for cardiovascular transplantation.Objective: To evaluate the occurrence of arrhythmias and cardiovascular changes during 6WT. To correlate 6WT performance with clinical staging and cardiovascular prognosis.Methods: Twelve patients, 10 of whom males, aged 52 ± 8 years were evaluated at baseline. 6WT was performed with telemetry electrocardiography, vital signs and lactate monitoring. The patients were followed-up for 12 months.Results: The patients walked 399.4±122.5 (D, m), reaching a perceived exertion (PE) of 14.3±1.5 and a 34% baseline heart rate variation. Two patients presented more severe pre-6WT arrhythmia which did not worsen with the exercice, four patients presented a significant increase of blood lactate levels (>5 mmol/dl), and three interrupted the test. The distance walked correlated with the ejection fraction (%) and functional class (NYHA). After 12-month follow-up, three patients died and seven were rehospitalized for cardiac decompensation. The D/PE ratio and 2-minute heart rate recovery (HRR2, bpm) were lower in the death group.Conclusion: The clinical and electrocardiographic behaviors suggest that the method is safe, but it may be considered too strenuous for some patients with severe heart failure. Variables related to 6WT performance may be associated with the one-year follow-up mortality. _______________________________________________________________________________________________________________ RESUMENFUNDAMENTO: El test de marcha de 6 minutos (TM6m) ha sido utilizado como forma de evaluación de la capacidad funcional, del estadiamiento clínico y el pronóstico cardiovascular. La seguridad y el impacto metabólico son poco descritos en la literatura, principalmente en pacientes con insuficiencia cardiaca severa e indicación clínica para transplante cardiovascular Objetivo: Evaluar la ocurrencia de arritmias y alteraciones cardiovasculares durante el TM6m. Correlacionar el desempeño en el TM6m con el estadiamiento clínico y el pronóstico cardiovascular. MÉTODOS: Un total de 12 pacientes, 10 varones, con edad de 52 ± 8 años, fueron sometidos a evaluación inicial. Realizaron el TM6m con monitoreo electrocardiográfico por telemetría, señales vitales y lactato. Se siguieron a los individuos por 12 meses. RESULTADOS: Los pacientes recorrieron 399,4 ± 122,5 (D, m), alcanzando un esfuerzo percibido (EP) de 14,3 ± 1,5 y variación del 34% en la frecuencia cardiaca basal. Dos pacientes presentaron arritmia de mayor severidad pre-TM6m y no mostraron empeoramiento ante el esfuerzo; cuatro tuvieron elevación significativa en los niveles de lactato sanguíneo (>5 mmol/dl), y tres interrumpieron el examen. La distancia recorrida evidenció correlación con la fracción de eyección (%) y la clasificación funcional (NYHA). Tras 12 meses de seguimiento, tres pacientes murieron, y siete se reinternaron por descompensación cardiaca. La relación (D/EP) y frecuencia cardiaca de recuperación en el segundo minuto (FCR2, lpm) fueron inferiores en el grupo óbito. CONCLUSIÓN: El comportamiento clínico y electrocardiográfico sugiere que el método es seguro, pero se puede considerarlo de alta intensidad para algunos pacientes con insuficiencia cardiaca severa. Variables relacionadas al desempeño en el TM6m pueden estar asociadas con la mortalidad en el seguimiento de un año

Evaluación de la seguridad de la test de marcha de 6 minutos en pacientes en el pre-transplante cardiaco

BACKGROUND: The 6-minute walk test (6WT) has been used as a means of assessment of the functional capacity, clinical staging and cardiovascular prognosis. Its safety and metabolic impact have not been frequently described in the literature, especially in patients with severe heart failure with clinical indication for cardiovascular transplantation. OBJECTIVE: To evaluate the occurrence of arrhythmias and cardiovascular changes during 6WT. To correlate 6WT performance with clinical staging and cardiovascular prognosis. METHODS: Twelve patients, 10 of whom males, aged 52 ± 8 years were evaluated at baseline. 6WT was performed with telemetry electrocardiography, vital signs and lactate monitoring. The patients were followed-up for 12 months. RESULTS: The patients walked 399.4±122.5 (D, m), reaching a perceived exertion (PE) of 14.3±1.5 and a 34% baseline heart rate variation. Two patients presented more severe pre-6WT arrhythmia which did not worsen with the exercice, four patients presented a significant increase of blood lactate levels (>5 mmol/dl), and three interrupted the test. The distance walked correlated with the ejection fraction (%) and functional class (NYHA). After 12-month follow-up, three patients died and seven were rehospitalized for cardiac decompensation. The D/PE ratio and 2-minute heart rate recovery (HRR2, bpm) were lower in the death group. CONCLUSION: The clinical and electrocardiographic behaviors suggest that the method is safe, but it may be considered too strenuous for some patients with severe heart failure. Variables related to 6WT performance may be associated with the one-year follow-up mortality.FUNDAMENTO: El test de marcha de 6 minutos (TM6m) ha sido utilizado como forma de evaluación de la capacidad funcional, del estadiamiento clínico y el pronóstico cardiovascular. La seguridad y el impacto metabólico son poco descritos en la literatura, principalmente en pacientes con insuficiencia cardiaca severa e indicación clínica para transplante cardiovascular Objetivo: Evaluar la ocurrencia de arritmias y alteraciones cardiovasculares durante el TM6m. Correlacionar el desempeño en el TM6m con el estadiamiento clínico y el pronóstico cardiovascular. MÉTODOS: Un total de 12 pacientes, 10 varones, con edad de 52 ± 8 años, fueron sometidos a evaluación inicial. Realizaron el TM6m con monitoreo electrocardiográfico por telemetría, señales vitales y lactato. Se siguieron a los individuos por 12 meses. RESULTADOS: Los pacientes recorrieron 399,4 ± 122,5 (D, m), alcanzando un esfuerzo percibido (EP) de 14,3 ± 1,5 y variación del 34% en la frecuencia cardiaca basal. Dos pacientes presentaron arritmia de mayor severidad pre-TM6m y no mostraron empeoramiento ante el esfuerzo; cuatro tuvieron elevación significativa en los niveles de lactato sanguíneo (>5 mmol/dl), y tres interrumpieron el examen. La distancia recorrida evidenció correlación con la fracción de eyección (%) y la clasificación funcional (NYHA). Tras 12 meses de seguimiento, tres pacientes murieron, y siete se reinternaron por descompensación cardiaca. La relación (D/EP) y frecuencia cardiaca de recuperación en el segundo minuto (FCR2, lpm) fueron inferiores en el grupo óbito. CONCLUSIÓN: El comportamiento clínico y electrocardiográfico sugiere que el método es seguro, pero se puede considerarlo de alta intensidad para algunos pacientes con insuficiencia cardiaca severa. Variables relacionadas al desempeño en el TM6m pueden estar asociadas con la mortalidad en el seguimiento de un año.FUNDAMENTO: O teste de caminhada dos 6 minutos (TC6) tem sido utilizado como forma de avaliação da capacidade funcional, estadiamento clínico e prognóstico cardiovascular. A segurança e o impacto metabólico são pouco descritos na literatura, principalmente em pacientes com insuficiência cardíaca grave, com indicação clínica para transplante cardiovascular. OBJETIVO: Avaliar a ocorrência de arritmias e alterações cardiovasculares durante o TC6. Correlacionar o desempenho no TC6 com o estadiamento clínico e prognóstico cardiovascular. MÉTODOS: Doze pacientes, sendo 10 masculinos, com idade de 52 ± 8 anos, foram submetidos à avaliação inicial. Realizaram o TC6 com monitoramento eletrocardiográfico por telemetria, sinais vitais e lactato. Foram acompanhados por 12 meses. RESULTADOS: Os pacientes percorreram 399,4 ± 122,5 (D, m), atingindo um esforço percebido (EP) de 14,3 ± 1,5 e variação de 34% na freqüência cardíaca basal. Dois pacientes apresentaram arritmia de maior gravidade pré-TC6 e não pioraram ante o esforço, quatro tiveram elevação significativa nos níveis de lactato sangüíneo (>5 mmol/dl), e três interromperam o exame. A distância percorrida evidenciou correlação com a fração de ejeção (%) e classificação funcional (NYHA). Após 12 meses de seguimento, três pacientes foram a óbito, e reinternaram-se sete por descompensação cardíaca. A relação (D/EP) e freqüência cardíaca de recuperação no segundo minuto (FCR2, bpm) foram inferiores no grupo-óbito. CONCLUSÃO: O comportamento clínico e eletrocardiográfico sugere que o método é seguro, mas pode ser considerado de alta intensidade para alguns pacientes com insuficiência cardíaca grave. Variáveis relacionadas ao desempenho no TC6 podem estar associadas com a mortalidade no seguimento de um ano.Universidade Federal de São Paulo (UNIFESP) Universidade de São PauloUNIFESP, Universidade de São PauloSciEL

Ceramic high temperature plate‐fin heat exchanger: A novel methodology for thermomechanical design investigation

The basic methodology of a novel, time-saving approach for critical thermomechanical design studies of ceramic high temperature plate fin heat exchanger is presented. This approach allows the determination of local displacements, by applying the outer heat exchanger boundary conditions on a substitute model. These displacements are then used for detailed calculation of local stresses. The methodology is based on the effective Young’s modulus, effective shear modulus and effective Poisson ratio. Simulation models have been developed to determine these effective substitute properties. A model verification has been performed with a compression test rig. The simulation predicts the experimental results with deviations below 3%, which proves the feasibility and reliability of the effective material models. In order to reduce the parametric effort of the substitute simulation model, information about the material behavior is important. Here, the results indicate an orthotropic material behavior of the fin structure. This reduces the independent substitute material properties required for the characterization of the substitute model, which also reduces the overall simulation time

Rationale, design and conduct of a randomised controlled trial evaluating a primary care-based complex intervention to improve the quality of life of heart failure patients: HICMan (Heidelberg Integrated Case Management) : study protocol

Background: Chronic congestive heart failure (CHF) is a complex disease with rising prevalence, compromised quality of life (QoL), unplanned hospital admissions, high mortality and therefore high burden of illness. The delivery of care for these patients has been criticized and new strategies addressing crucial domains of care have been shown to be effective on patients' health outcomes, although these trials were conducted in secondary care or in highly organised Health Maintenance Organisations. It remains unclear whether a comprehensive primary care-based case management for the treating general practitioner (GP) can improve patients' QoL. Methods/Design: HICMan is a randomised controlled trial with patients as the unit of randomisation. Aim is to evaluate a structured, standardized and comprehensive complex intervention for patients with CHF in a 12-months follow-up trial. Patients from intervention group receive specific patient leaflets and documentation booklets as well as regular monitoring and screening by a prior trained practice nurse, who gives feedback to the GP upon urgency. Monitoring and screening address aspects of disease-specific selfmanagement, (non)pharmacological adherence and psychosomatic and geriatric comorbidity. GPs are invited to provide a tailored structured counselling 4 times during the trial and receive an additional feedback on pharmacotherapy relevant to prognosis (data of baseline documentation). Patients from control group receive usual care by their GPs, who were introduced to guidelineoriented management and a tailored health counselling concept. Main outcome measurement for patients' QoL is the scale physical functioning of the SF-36 health questionnaire in a 12-month follow-up. Secondary outcomes are the disease specific QoL measured by the Kansas City Cardiomyopathy questionnaire (KCCQ), depression and anxiety disorders (PHQ-9, GAD-7), adherence (EHFScBS and SANA), quality of care measured by an adapted version of the Patient Chronic Illness Assessment of Care questionnaire (PACIC) and NTproBNP. In addition, comprehensive clinical data are collected about health status, comorbidity, medication and health care utilisation. Discussion: As the targeted patient group is mostly cared for and treated by GPs, a comprehensive primary care-based guideline implementation including somatic, psychosomatic and organisational aspects of the delivery of care (HICMAn) is a promising intervention applying proven strategies for optimal care. Trial registration: Current Controlled Trials ISRCTN30822978